scholarly journals Loss of IL-10 signaling promotes IL-22 dependent host defenses against acute Clostridioides difficile infection

2021 ◽  
Author(s):  
Emily S. Cribas ◽  
Joshua E. Denny ◽  
Jeffrey R. Maslanka ◽  
Michael C. Abt
Keyword(s):  
Defense Mechanisms ◽  
Intestinal Inflammation ◽  
Bacterial Pathogen ◽  
Survival Advantage ◽  
Protective Mechanisms ◽  
Genetic Ablation ◽  
Proinflammatory Mediators ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
The Impact

Infection with the bacterial pathogen Clostridioides difficile causes severe damage to the intestinal epithelium that elicits a robust inflammatory response. Markers of intestinal inflammation accurately predict clinical disease severity. However, determining the extent to which host-derived proinflammatory mediators drive pathogenesis versus promote host protective mechanisms remains elusive. In this report, we employed Il10-/- mice as a model of spontaneous colitis to examine the impact of constitutive intestinal immune activation, independent of infection, on C. difficile disease pathogenesis. Upon C. difficile challenge, Il10-/- mice exhibited significantly decreased morbidity and mortality compared to littermate Il10 heterozygote (Il10HET) control mice, despite a comparable C. difficile burden, innate immune response, and microbiota composition following infection. Similarly, antibody-mediated blockade of IL-10 signaling in wild-type C57BL/6 mice conveyed a survival advantage if initiated three weeks prior to infection. In contrast, no advantage was observed if blockade was initiated on the day of infection, suggesting that constitutive activation of inflammatory defense pathways prior to infection mediated host protection. IL-22, a cytokine critical in mounting a protective response against C. difficile infection, was elevated in the intestine of uninfected, antibiotic-treated Il10-/- mice, and genetic ablation of the IL-22 signaling pathway in Il10-/- mice negated the survival advantage following C. difficile challenge. Collectively, these data demonstrate that constitutive loss of IL-10 signaling, via genetic ablation or antibody blockade, enhances IL-22 dependent host defense mechanisms to limit C. difficile pathogenesis.

scholarly journals Loss of IL-10 signaling promotes IL-22 dependent host defenses against acute Clostridioides difficile infection

2020 ◽  
Author(s):  
Emily S. Cribas ◽  
Joshua E. Denny ◽  
Jeffrey R. Maslanka ◽  
Michael C. Abt
Keyword(s):  
Defense Mechanisms ◽  
Intestinal Inflammation ◽  
Bacterial Pathogen ◽  
Survival Advantage ◽  
Protective Mechanisms ◽  
Genetic Ablation ◽  
Proinflammatory Mediators ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
The Impact

AbstractInfection with the bacterial pathogen Clostridioides difficile causes severe damage to the intestinal epithelium that elicits a robust inflammatory response. Markers of intestinal inflammation accurately predict clinical disease severity. However, determining the extent to which host-derived proinflammatory mediators drive pathogenesis versus promote host protective mechanisms remains elusive. In this report, we employed Il10-/- mice as a model of spontaneous colitis to examine the impact of constitutive intestinal immune activation, independent of infection, on C. difficile disease pathogenesis. Upon C. difficile challenge, Il10-/- mice exhibited significantly decreased morbidity and mortality compared to littermate Il10 heterozygote (Il10HET) control mice, despite a comparable C. difficile burden, innate immune response, and microbiota composition following infection. Similarly, antibody-mediated blockade of IL-10 signaling in wild-type C57BL/6 mice conveyed a survival advantage if initiated three weeks prior to infection. In contrast, no advantage was observed if blockade was initiated on the day of infection, suggesting that constitutive activation of inflammatory defense pathways prior to infection mediated host protection. IL-22, a cytokine critical in mounting a protective response against C. difficile infection, was elevated in the intestine of uninfected, antibiotic-treated Il10-/- mice, and genetic ablation of the IL-22 signaling pathway in Il10-/- mice negated the survival advantage following C. difficile challenge. Collectively, these data demonstrate that constitutive loss of IL-10 signaling, via genetic ablation or antibody blockade, enhances IL-22 dependent host defense mechanisms to limit C. difficile pathogenesis.

scholarly journals Fecal microbiota transplantation increases colonic IL-25 and dampens tissue inflammation in patients with recurrent Clostridioides difficile

2021 ◽  
Author(s):  
Ning-Jiun Jan ◽  
Noah Oakland ◽  
Pankaj Kumar ◽  
Girija Ramakrishnan ◽  
Brian W. Behm ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Fecal Microbiota Transplantation ◽  
Alpha Diversity ◽  
The United States ◽  
Fecal Microbiota ◽  
Peripheral Blood Mononuclear ◽  
Clostridioides Difficile ◽  
Rdna Sequencing ◽  
Clostridioides Difficile Infection ◽  
The Impact

Background: Clostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of IL-25, and that FMT protected in part by restoring gut commensal bacteria-mediated IL-25 signaling. Here we conducted a prospective clinical trial to test the impact of FMT on immunity, specifically testing in humans if FMT induced IL-25 expression in the colon. Methods: Subjects received colonic biopsies and blood sampling at the time of FMT and 60-days later. Colon biopsies were assayed for IL-25 by immunoassay, for mRNA by RNAseq, and for bacterial content by 16 S rDNA sequencing. High dimensional flow cytometry was also conducted on peripheral blood mononuclear cells pre- and post-FMT. Results: All 10 subjects who received FMT had no CDI recurrences over a 2 year follow-up post FMT. FMT increased alpha diversity of the colonic microbiota and was associated with several immunologic changes. The cytokine IL-25 was increased in colonic tissue. In addition, increased expression of homeostatic genes and repression of inflammatory genes was observed in colonic mRNA transcripts. Finally, circulating Th17 cells were decreased post-FMT. Conclusion: The increase in the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity.

scholarly journals 2373. Impact of a Change in Testing Strategy for Clostridioides difficile Infection on a Publicly Reported Metric and Treatment Days of Therapy

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S818-S819
Author(s):  
Ryan Miller ◽  
Jose A Morillas ◽  
Joanne Sitaras ◽  
Jacob Bako ◽  
Elizabeth A Neuner ◽  
...  
Keyword(s):  
Health System ◽  
Diagnostic Testing ◽  
Cleveland Clinic ◽  
Public Reporting ◽  
Testing Strategy ◽  
Clostridioides Difficile ◽  
Days Of Therapy ◽  
Before And After ◽  
Clostridioides Difficile Infection ◽  
The Impact

Abstract Background In an effort to optimize diagnostic testing for Clostridioides difficile infection (CDI) our health system changed from stand-alone PCR testing to a “2-step” approach wherein all positive PCR results reflexed to an EIA. We report the effects of this change on publicly reported CDI metrics and treatment days of therapy (DOT). Methods The setting includes 10 Cleveland Clinic Health System hospitals in northeast Ohio and one in Florida. On June 12, 2018, 9 NE Ohio hospitals changed from PCR alone to PCR followed by EIA. Stand-alone PCR testing remained at one and GDH / EIA / PCR for discordant for another. Testing volumes were obtained from the microbiology laboratory. C. difficile LabID event SIRs were obtained from NHSN. Public reporting interpretative categories were identified based on SIR for second half of 2018. DOT for CDI agents were obtained from an antimicrobial stewardship database. Results Among hospitals that changed strategy the volume of PCR testing and the percent PCR + was similar between time periods. EIA positivity ranged from 23% to 53%. 4/11 hospitals improved their public reporting category: 3/9 that changed testing strategy and 1/2 that did not (Table 1). Two of 3 that changed strategy and improved public reporting also had a decrease in DOT. DOT increased in the 2 hospitals that did not change strategy. Conclusion Six months after adopting a 2-step CDI testing strategy 7 of 9 hospitals had a lower SIR with 3 also demonstrating an improvement in public reporting category favorably impacting reputational and reimbursement risk for our healthcare system. CDI agent DOT was similar before and after the change. The impact of choice of test on publicly reported metrics demonstrates the difficulty of utilizing a proxy for hospital onset CDI, the CDI LabID event, as a measure of quality of care provided. Disclosures All authors: No reported disclosures.

scholarly journals 2440. Using a geospatially explicit agent-based model of a regional healthcare network to assess varied antibiotic risk on Clostridioides difficile infection incidence

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S843-S844
Author(s):  
Sarah Rhea ◽  
Kasey Jones ◽  
Georgiy Bobashev ◽  
Breda Munoz ◽  
James Rineer ◽  
...  
Keyword(s):  
Acute Care ◽  
Acute Care Hospital ◽  
Care Hospital ◽  
Healthcare Facilities ◽  
Agent Based ◽  
Healthcare Network ◽  
Clostridioides Difficile ◽  
Unit Increase ◽  
Clostridioides Difficile Infection ◽  
The Impact

Abstract Background Different antibiotic classes are associated with different Clostridioides difficile infection (CDI) risk. The impact of varied antibiotic risk on CDI incidence can be explored using agent-based models (ABMs). ABMs can simulate complete systems (e.g., regional healthcare networks) comprised of discrete, unique agents (e.g., patients) which can be represented using a synthetic population, or model-generated representation of the population. We used an ABM of a North Carolina (NC) regional healthcare network to assess the impact of increasing antibiotic risk ratios (RRs) across network locations on healthcare-associated (HA) and community-associated (CA) CDI incidence. Methods The ABM describes CDI acquisition and patient movement across 14 network locations (i.e., nodes) (11 short-term acute care hospitals, 1 long-term acute care hospital, 1 nursing home, and the community). We used a sample of 2 million synthetic NC residents as ABM microdata. We updated agent states (i.e., location, antibiotic exposure, C. difficile colonization, CDI status) daily. We applied antibiotic RRs of 1, 5, 8.9 (original model RR), 15, and 20 to agents across the network to simulate varied risk corresponding to different antibiotic classes. We determined network HA-CDI and CA-CDI incidence and percent mean change for each RR. Results In this simulation study, HA-CDI incidence increased with increasing antibiotic risk, ranging from 11.3 to 81.4 HA-CDI cases/100,000 person-years for antibiotic RRs of 1 to 20, respectively. On average, the per unit increase in antibiotic RR was 33% for HA-CDI and 6% for CA-CDI (figure). Conclusion We used a geospatially explicit ABM to simulate increasing antibiotic risk, corresponding to different antibiotic classes, and to explore the impact on CDI incidence. The per unit increase in antibiotic risk was greater for HA-CDI than CA-CDI due to the higher probability of receiving antibiotics and higher concentration of agents with other CDI risk factors in the healthcare facilities of the ABM. These types of analyses, which demonstrate the interconnectedness of network healthcare facilities and the associated community served by the network, might help inform targeted antibiotic stewardship efforts in certain network locations. Disclosures All authors: No reported disclosures.

scholarly journals 2389. Assessing the Time Course of Proton Pump Inhibitor Use and Clostridioides difficile Infection

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S825-S825
Author(s):  
Katherine Panagos ◽  
Natalia Blanco ◽  
Surbhi Leekha ◽  
Erik von Rosenvinge ◽  
Emily Heil
Keyword(s):  
Proton Pump ◽  
Time Course ◽  
Conditional Logistic Regression ◽  
Academic Medical Center ◽  
Antibiotic Use ◽  
Clostridioides Difficile ◽  
Increased Risk ◽  
Significant Difference ◽  
Clostridioides Difficile Infection ◽  
The Impact

Abstract Background Proton pump inhibitors (PPIs) are a known risk factor for Clostridioides difficile infection (CDI) and recurrence, even in the absence of antibiotic use. No studies have specifically assessed the increased risk for CDI based on PPI duration, given that PPIs are frequently newly prescribed during hospitalizations and infrequently discontinued, even when CDI has occurred. The aim of this project was to assess the time course of PPI utilization and risk of CDI. Methods We conducted a retrospective matched case–control study comparing patients who developed CDI (cases) with patients who did not develop CDI (controls, matched on age, gender, date of admission and hospital location) from a cohort of patients with a C.difficile PCR test order from an academic medical center. Patient charts were reviewed for PPI use prior to the date of the positive test and whether the PPI was started in the hospital or as a home medication (>30d, 30–90d, 90–180d, >180d). The primary comparison was odds of PPI use between cases and controls using conditional logistic regression adjusted for antibiotic exposure (SAS 9.4, Cary, NC). Results A total of 348 patients were included in the study, 174 cases and 174 matched controls. 65% of patients in the study received a PPI, 85% a PPI or H2 blocker and 95% of patients received antibiotics during their admission. Patients on PPIs as home medications were not at an increased risk of CDI (OR = 1.08 (95% CI 0.60–1.93)) compared with those not on PPIs. Patients whose PPIs were initiated in the hospital were at increased risk of CDI compared with those not on PPIs (OR = 1.4 (95% CI 0.81–2.41)). No significant difference was observed across time periods of PPI use prior to admission and development of CDI. Conclusion Patients who started PPIs during inpatient stays were at a higher risk of developing CDI than patients not exposed to PPIs. However, PPI use was not found to be significantly associated with CDI in this analysis, regardless of the time or duration of PPI prescription. The results may be confounded by the high frequency of PPI use and concomitant antibiotic use in both cases and controls. Further study is needed to evaluate the impact of short-course PPI prescriptions in inpatient settings on CDI. Disclosures All authors: No reported disclosures.

scholarly journals The impact of an electronic medical record nudge on reducing testing for hospital-onset Clostridioides difficile infection

2020 ◽  
Vol 41 (4) ◽  
pp. 411-417 ◽  
Author(s):  
Jessica R. Howard-Anderson ◽  
Mary Elizabeth Sexton ◽  
Chad Robichaux ◽  
Zanthia Wiley ◽  
Jay B. Varkey ◽  
...  
Keyword(s):  
Medical Record ◽  
Electronic Medical Record ◽  
Interrupted Time Series ◽  
Interrupted Time Series Analysis ◽  
Level Change ◽  
Order Rate ◽  
Clostridioides Difficile ◽  
Stool Softener ◽  
Clostridioides Difficile Infection ◽  
The Impact

AbstractObjective:To determine the effect of an electronic medical record (EMR) nudge at reducing total and inappropriate orders testing for hospital-onset Clostridioides difficile infection (HO-CDI).Design:An interrupted time series analysis of HO-CDI orders 2 years before and 2 years after the implementation of an EMR intervention designed to reduce inappropriate HO-CDI testing. Orders for C. difficile testing were considered inappropriate if the patient had received a laxative or stool softener in the previous 24 hours.Setting:Four hospitals in an academic healthcare network.Patients:All patients with a C. difficile order after hospital day 3.Intervention:Orders for C. difficile testing in patients administered a laxative or stool softener in <24 hours triggered an EMR alert defaulting to cancellation of the order (“nudge”).Results:Of the 17,694 HO-CDI orders, 7% were inappropriate (8% prentervention vs 6% postintervention; P < .001). Monthly HO-CDI orders decreased by 21% postintervention (level-change rate ratio [RR], 0.79; 95% confidence interval [CI], 0.73–0.86), and the rate continued to decrease (postintervention trend change RR, 0.99; 95% CI, 0.98–1.00). The intervention was not associated with a level change in inappropriate HO-CDI orders (RR, 0.80; 95% CI, 0.61–1.05), but the postintervention inappropriate order rate decreased over time (RR, 0.95; 95% CI, 0.93–0.97).Conclusion:An EMR nudge to minimize inappropriate ordering for C. difficile was effective at reducing HO-CDI orders, and likely contributed to decreasing the inappropriate HO-CDI order rate after the intervention.

Trends in the incidence and outcomes of Clostridioides difficile infection in hematological cancers: A nationwide analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18244-e18244
Author(s):  
Fateeha Furqan ◽  
Raseen Tariq ◽  
Nicolas Goldstein ◽  
Sanjana Kashinath ◽  
Saad Jamshed ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Hematologic Malignancy ◽  
Care Facility ◽  
Healthcare Facility ◽  
National Hospital Discharge Survey ◽  
Clostridioides Difficile ◽  
Hematologic Cancer ◽  
Hematological Cancers ◽  
Clostridioides Difficile Infection ◽  
The Impact

e18244 Background: Clostridioides difficile infection (CDI) has higher incidence in cancer patients. To characterize the extent of CDI burden among hematologic cancer patients, we used the National Hospital Discharge Survey (NHDS) to report the incidence and outcomes of CDI. Methods: NHDS data from 2001-2010 were analyzed using diagnosis codes to identify patients with hematologic cancers and CDI. Demographics and discharge information were compared amongst hematologic cancer patients with and without CDI. Logistic regression models were runto estimate the impact of CDI on hematologic cancer patient outcomes, using STATA 12.0. Results: During the years 2001-2010, about 3.7 million patients (weighted data) were discharged with hematologic cancer. Among them, the incidence of CDI was 2.3%. Hematologic cancer patients with CDI were younger (mean age 66 vs 68 years), more likely to be men (66% vs 64.5%), to be of white race (68.1% vs 67.7%) and to have emergent admissions (73% vs 69%), all p values < 0.001. CDI incidence in these patients showed a steeper increase than non-cancer patients, with highest incidence in 2008-2009. Hematologic cancer patients with CDI had a longer mean Length of stay (16.9 vs 7.1 days; adjusted odds ratio (aOR) 9.5, 95% CI 9.4-9.6), all cause hospital mortality (11.3% vs 6.3%; aOR 1.92, 95% CI 1.88-1.97) and discharge to a care facility (28.4% vs 18.8%; aOR 2.06, 95% CI 2.02-2.10) compared to non-CDI cancer patients. Conclusions: CDI incidence is higher in patients with hematologic malignancy. They also have worse outcomes including overall mortality, longer hospitalizations and discharge to healthcare facility. These patients warrant closer screening and prompt treatment of CDI as they are at greater risk of unfavorable outcomes. [Table: see text]

scholarly journals Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease

2012 ◽  
Vol 303 (6) ◽  
pp. L528-L538 ◽  
Author(s):  
Sidra M. Hoffman ◽  
Jane E. Tully ◽  
Karolyn G. Lahue ◽  
Vikas Anathy ◽  
James D. Nolin ◽  
...  
Keyword(s):  
Allergic Inflammation ◽  
Protein S ◽  
Redox Status ◽  
Oxidative Modification ◽  
Genetic Ablation ◽  
Proinflammatory Mediators ◽  
Enhanced Resolution ◽  
Important Player ◽  
The Impact ◽  
Mucus Metaplasia

Protein- S-glutathionylation (PSSG) is an oxidative modification of reactive cysteines that has emerged as an important player in pathophysiological processes. Under physiological conditions, the thiol transferase, glutaredoxin-1 (Glrx1) catalyses deglutathionylation. Although we previously demonstrated that Glrx1 expression is increased in mice with allergic inflammation, the impact of Glrx1/PSSG in the development of allergic airways disease remains unknown. In the present study we examined the impact of genetic ablation of Glrx1 in the pathogenesis of allergic inflammation and airway hyperresponsiveness (AHR) in mice. Glrx1 −/− or WT mice were subjected to the antigen, ovalbumin (OVA), and parameters of allergic airways disease were evaluated 48 h after three challenges, and 48 h or 7 days after six challenges with aerosolized antigen. Although no clear increases in PSSG were observed in WT mice in response to OVA, marked increases were detected in lung tissue of mice lacking Glrx1 48 h following six antigen challenges. Inflammation and expression of proinflammatory mediators were decreased in Glrx1 −/− mice, dependent on the time of analysis. WT and Glrx1 −/− mice demonstrated comparable increases in AHR 48 h after three or six challenges with OVA. However, 7 days postcessation of six challenges, parameters of AHR in Glrx1 −/− mice were resolved to control levels, accompanied by marked decreases in mucus metaplasia and expression of Muc5AC and GOB5. These results demonstrate that the Glrx1/ S-glutathionylation redox status in mice is a critical regulator of AHR, suggesting that avenues to increase S-glutathionylation of specific target proteins may be beneficial to attenuate AHR.

Evaluating Clostridioides difficile infection (CDI) treatment duration in hematology/oncology patients receiving concurrent non-CDI antibiotics

2021 ◽  
pp. 107815522199873
Author(s):  
Kelli R Keats ◽  
Tia M Stitt ◽  
Daniel B Chastain ◽  
Bhaumik P Jivan ◽  
Elizabeth Matznick ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Primary Outcome ◽  
Hospital Length ◽  
Hospital Length Of Stay ◽  
Oncology Patients ◽  
Clostridioides Difficile ◽  
Standard Duration ◽  
Clostridioides Difficile Infection ◽  
Extended Analysis ◽  
The Impact

Purpose To determine the impact of Clostridioides difficile infection (CDI) treatment duration on CDI recurrence in hematology/oncology patients receiving concurrent non-CDI antibiotics. Patients and methods This multi-site, retrospective study examined hematology/oncology patients age ≥18 years hospitalized with active CDI who received ≥1 dose of concurrent non-CDI antibiotics between September 2013 and June 2019. All patients were classified by two definitions for statistical analysis: standard (10-14 days) versus prolonged (>14 days) duration of CDI treatment and non-extended (≤24 hours after stopping non-CDI antibiotics) versus extended (>24 hours after stopping non-CDI antibiotics) CDI treatment. Primary outcome was CDI recurrence within 180 days of completing CDI treatment. Secondary outcomes included hospital length of stay (LOS) as well as mortality and incidence of vancomycin-resistant enterococcus (VRE) infections at 180 days. Results Of the 198 patients included, 112 were classified as prolonged versus 86 standard duration and 138 were classified as extended versus 60 non-extended duration. After accounting for demographic differences, no difference existed in the primary outcome of CDI recurrence in either prolonged versus standard or extended versus non-extended analysis (all p > 0.05). Patients who received prolonged versus standard CDI treatment had longer LOS (p < 0.0001) while no difference existed in extended versus non-extended (p > 0.05). No difference in mortality existed in prolonged versus standard (p > 0.05) while those who received extended versus non-extended CDI treatment had significantly lower mortality (p = 0.0008). Conclusions Neither prolonging CDI treatment beyond standard duration nor extending duration beyond end of non-CDI antibiotics was associated with decreased CDI recurrence rate.

Sign in / Sign up

Export Citation Format

Share Document